Amine prodrugs of pharmaceutical compounds

ABSTRACT

Disclose are amine prodrugs and methods of synthesis thereof. In particular, the amine prodrug comprises a drug molecule and at least one or more prodrug appendage moieties and the method for synthesis the amine prodmg comprises a step of coupling the drag molecule and at least one or more prodrug appendage moieties. Also disclosed are exemplary riluzole prodrugs and methods of synthesis thereof.

CROSS REFERENCE TO RELATED A.PPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 62/257,533 filed Nov. 19, 2015, the disclosure ofwhich is herein incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to amine prodrugs and methods of synthesisthereof. The amine prodrug comprises a drug molecule and at least one ormore prodrug appendage moieties. The method of synthesis thereofcomprises a step of coupling the drug molecule and at least one or moreprodrug appendage moieties.

BACKGROUND

Discovery of novel prodrugs has been an integral part in currentpharmaceutical industry. A prodrug is an alternative form of a drug andis used instead to improve absorbed, distributed, metabolized andexcreted (ADME) properties of the drug. The prodrug is administered inan inactive or less active form, and is subsequently converted to itsactive drug through a normal metabolic process, such as hydrolysis orother chemical reactions, in a subject.

Among commercially available prodrug products, amine prodrugs such asCapecitabine (Xeloda), Docarpamine, Prulifloxacin, Gabapentin enacabril,and Altrofloxacin have been successfully introduced into market. Theprimary or secondary amine prodrugs have been made substantially andfurther prodrugs of tertiary amine or quaternary amine have been alsomade and are being advanced into clinical development as well. (Prodrugsof Amines, Ana L. Simphcio et al, Molecules, 2008,13 519-547; Prodrugsof Amines, Jeffrey Krise et al, Prodrugs, Challenges and Rewards Part 1and Part 2, Springer N.Y., 2007; Drug Synthesis II, presentation byTapio Nevalainen, University of Eastern Finland, 2012.)

As such, other amine prodrugs are potential candidates for drugdevelopment.

SUMMARY OF THE INVENTION

The present invention provides amine prodrug and methods of synthesisthereof.

In one aspect, the present invention provides a prodrug which comprisesa drug molecule and at least one or more prodrug appendage moieties. Theprodrug may be as:

In particular, the prodrug appendage moiety may be coupled to amine ofthe drug molecule. In this prodrug of the present invention, i may be 1or 2 and j may be 0 or 1. For example, i is 1 and j is 1; or i is 2 andj is 0.

The prodrug appendage moiety may be independently selected from thegroup of consisting of:

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl;

R² may be alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, whichmay be substituted or unsubstituted.

R³ may be H, metal, R² or a substituted or unsubstituted primary,secondary or tertiary amine;

R⁴ may be H, metal, ammonium salt, or alkyl;

R⁵ may be a substituted or unsubstituted natural amino acid;

R^(a) or R^(b) may be H, alkyl or aryl; or NR^(a) or NR^(b) may be anamino acid;

X may be C or O;

k may be 1 or 2, m may be 2-22, or (CH_(k))_(m) may be saturated,unsaturated or conjugated hydrocarbon;

n may be 0-2; and

the metal may be Na, K, Li, Ca, Mg, Ag or Zn.

In an exemplary embodiment, and the drug molecule may be riluzole.

In another aspect, the present invention provides a method of preparinga prodrug.

In one embodiment, a method of preparing a riluzole prodrug is provided.The method comprises a step of coupling one or more prodrug appendagemoieties to a riluzole molecule as described below.

In particular, the prodrug appendage moiety may be coupled to amine ofthe riluzole molecule where i may be 1 or 2 and j may be 0 or 1. Forexample, i is 1 and j is 1; or i is 2 and j is 0.

The prodrug appendage mu e independently selected from the group ofconsisting of:

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl;

R² may be alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, whichmay be substituted or unsubstituted.

R³ may be H, metal, R² or a substituted or unsubstituted primary,secondary or tertiary amine;

R⁴ may be H, metal, ammonium salt, or alkyl;

R⁵ may be a substituted or unsubstituted natural amino acid;

R^(a) or R^(b) may be H, alkyl or aryl; or NR^(a) or NR^(b) may be anamino acid;

X may be C or O;

k may be 1 or 2, in may be 2-22, or (CH_(k))_(m) may be saturated,unsaturated or conjugated hydrocarbon;

n may be 0-2; and

the metal may be Na, K, Li, Ca, Mg, Ag or Zn.

Exemplary riluzole prodrug may be:

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; R² may be alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; R³ may be H, metal, R² or a substituted orunsubstituted primary, secondary or tertiary amine; R⁴ may be H, metal,ammonium salt, or alkyl; R⁶ may be alkyl, cycloalkyl, aryl, orheteroaryl, or halo alkyl; N′ may be a primary, secondary and tertiaryamine which may be substituted or unsubstituted, or metal salts; and Ymay be PO₃H, CH₂PO₂H or salt thereof. In particular, the metal may beNa, K, Li, Ca, Mg, Ag or Zn.

The present invention also provides a method of synthesizing a riluzoleprodrug.

In one embodiment, the method comprises a step of reacting riluzole with

to produce

The method further comprises a step of reacting

with a compound selected from the group consisting of:

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl;

R² may be alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, whichmay be substituted or unsubstituted;

R⁴ may be H, metal, ammonium salt, or alkyl;

k may be 1 or 2, m may be 2-22, or (CH_(k))_(m) may be saturated,unsaturated or conjugated hydrocarbon;

Bc may be a protecting group;

Y′ may be H, PO₃Bc₂, CH₂PO₂Bc, MPO₃Bc or salt thereof, or N(R_(a))₂,where Ra is H or alkyl;

M may be a metal such as Na, K, Li, Ca, Mg, Ag or Zn; and

R′ or R″ may be cyclic or acyclic alkyl.

In one embodiment, the method of synthesizing a riluzole prodrugcomprises a step of reacting a riluzole, with CO₂, Cs₂CO₃ and reactingthe resulting compound with

wherein Lg is a leaving group.

In one embodiment, the method of synthesizing a riluzole prodrugcomprises a step of reacting a riluzole with

wherein Lg is a leaving group and where R¹ may be H, or C₁-C₈ alkyl

In one embodiment, the method of synthesizing a riluzole prodrugcomprises a step of reacting a riluzole with

wherein Lg is a leaving group.

In one embodiment, the method of synthesizing a riluzole prodrugcomprises a step of reacting riluzole with

wherein R¹ may be H, alkyl or particularly C₁-C₈ alkyl;

R² may be alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, whichmay be substituted or unsubstituted; and

R³ may be H, metal, R² or a substituted or unsubstituted primary,secondary or tertiary amine.

In one embodiment, the method of synthesizing a riluzole prodrugcomprises a step of reacting riluzole with ((PhCH₂O)₂PO)₂O and sodiumbis(trimethylsilyl)amide (NaHMDS) and subsequently reacting theresulting compound with hydrogen:

where R⁶ may be alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl;and N′ may be a primary, secondary and tertiary amine which may besubstituted or unsubstituted, or metal salts.

Other aspects of the invention are disclosed infra.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed, description provided to aid those skilledin the art in practicing the present invention. These of ordinary skillin the art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs. The terminology used in the description is for describingparticular embodiments only and is not intended to be limiting. Allpublications, patent applications, patents, figures and other referencesmentioned herein are expressly incorporated by reference in theirentirety.

The following terms are used to describe the present invention. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

As used in the description of the invention and the appended claims, thesingular forms “a”, “an” and “the” are used interchangeably and intendedto include the plural forms as well and fall within each meaning, unlessthe context clearly indicates otherwise. Also, as used herein, “and/or”refers to and encompasses any and all possible combinations of one ormore of the listed items, as well as the lack of combinations wheninterpreted in the alternative (“or”). Singular word forms are intendedto include plural word forms and are likewise used hereininterchangeably where appropriate and fall within each meaning, unlessexpressly stated otherwise.

The term “prodrug” as used herein, is a precursor of a drug which may beadministered in an altered or less active form. The prodrug may beconverted into the active drug form in physiological environments byhydrolysis or other metabolic pathways. The prodrug may provide improvedphysiochemical or physiological characteristics to enhance therapeuticeffects of the drug.

The term “prodrug appendage moiety” as used herein, refers to a chemicalgroup or moiety covalently or non-covalently attached to a drugmolecule, thereby produce a prodrug form of the drug. The prodrugappendage moiety may not alter pharmacokinetic core or properties of thedrug molecules by intramolecular rearrangement or cleavage. In certainembodiments, multiple prodrug appendage moieties may be attached to thedrug molecule, without limitation. In addition, the prodrug appendagemoiety may couple one or more of the drug molecules, without limitation.

The term “riluzole”, as used herein, refers to a drug,6-(trifluoromethoxy)benzothiazol-2-amine, which is generally used totreat amyotrophic lateral sclerosis (ALS). It is also available in themarket as RILUTEK®.

As used herein, the term “leaving group,” or “LG”, as used herein,refers to any group that leaves in the course of a chemical reactioninvolving the group and includes but is not limited to halogen,brosylate, mesylate, tosylate, tritlate, p-nitrobenzoate, phosphonategroups, for example,

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 18 (e.g., C₁-C-₁₈, inclusive;and any sub-range thereof) carbon atoms. The term “lower alkyl” refersto a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl (n-, sec-,tert-), and pivaloyl. Alkyl groups may be optionally substituted withone or more substituents.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or spirobicyclic groups e.g spiro(4,4)non-2-yl.

As used herein, the term “halogen” or “halide” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means and alkyl group in which oneor more (including all) the hydrogen radicals are replaced by a halogroup, wherein each halo group is independently selected from —F, —Cl,—Br, and —I. The term “halomethyl” means a methyl in which one to threehydrogen radical(s) have been replaced by a halo group. Representativehaloalkyl groups include trifluoromethyl, difluoromethyl, bromethyl,1,2-dichloreethyl, 4-iodobutyl, 2-fluoropentyl, and the like. The term“perhaloalkyl” refers to a alkyl group in which all hydrogen atoms arereplaced by a halo group (e.g., trifluoromethyl, pentafluoroethyl). Incertain embodiments, the haloalkyl may be an activated alkyl.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one non-aromaticring. Cycloalkyl groups may be optionally substituted with one or moresubstituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring ofa cycloalkyl group may be substituted by a substituent. Representativeexamples of cycloalkyl group include cyclopropyl, cyclopentyl,cyclohexyl, cyclobutyl, cycloheptyl, cyclooctyl, cyclononyl, andcyclodecyl.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term “heteroaryl” refers to an aromatic monocyclic, bicyclic, ortricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, and the remainder ring atoms beingcarbon (with appropriate hydrogen atoms unless otherwise indicated).Heteroaryl groups may be optionally substituted with one or moresubstituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring ofa heteroaryl group may be substituted by a substituent. Examples ofheteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl,benzol[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl,oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl,thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl,indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl,benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl,azaindolyl, imidazopyridyl, quinazolinyl, purinyl,pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl,3H-thiazolo[2,3c][1,2,4]thiadiazolyl, imidazo[1,2-d]-1,2,4-thiadiazolyl,imidazo[2,1-b]-1,3,4-thiadiazolyl. 1H,2H-furo[3,4-d]-1,2,3-thiadiazolyl,1H-pyrazolo[5,1-c]-1,2,4-triazolyl, pyrrolo[3,4-d]-1,2,3 triazolyl,cyclopentatriazolyl, 3H-pyrrolo[3,4-c]isoxazolyl,1H,3H-pyrrolo[1,2-c]oxazolyl, pyrrolol[2,1b]oxazolyl, and the like.

As used herein the term “substituent” or “substituted” means that ahydrogen radical on a compound or group (such as, for example, alkyl,alkenyl, alkynyl, alkylene, aryl aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cyclyl, heterocycloalkyl, or heterocyclyl group) is replacedwith any desired group that does not substantially adversely affect thestability of the compound. In one embodiment, desired substituents arethose which do not adversely affect the activity of a compound. The term“substituted” refers to one or more substituents (which may be the sameor different), each replacing a hydrogen atom. Examples of substituentsinclude, but are not limited to, halogen (F, Cl, Br, or I), hydroxyl,amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro,mercapto, oxo (i.e., carbonyl), thio, imino, formyl, carbamido,carbamyl, carboxyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl,sulfonylaryl, alkyl, alkenyl, alkoxy, mercaptoalkoxy, aryl, heteroaryl,cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkyloxy, aryl,heteroaryl, cyclyl, and heterocyclyl are optionally substituted withalkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano,nitro, oxo (═O), thioxo (═S), or imino (═NR), wherein R is as definedherein. The substituents on any group (such as, for example, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroaralkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl) canbe at any atom of that group, wherein any group that can be substituted(such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl,beteroaryl, beteroaralkyl, cycloalkyl, cyclyl, heterocycloalkyl, andheterocyclyl) can be optionally substituted with one or moresubstituents (which may be the same or different), each replacing ahydrogen atom. Examples of suitable substituents include, but notlimited to alkyl, alkenyl, alkynyl, cyclyl, cycloalkyl,heterocycloalkenyl, heterocycloalkyl, arylalkyl, beteroarylalkyl, aryl,heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl,hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl,alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl,heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl,arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino,alkylaminocarbonyl, or alkoxycarbonylamino; alkylamine, arylamino,diarylamino, alkylcarbonyl, or arylamino-substituted aryl;arylalkylamino, aralkylaminocarbonyl, amino, alkylaminosulfonyl,arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, imino, carbamido, carbamyl, thioureido, thiocyanato,sulfoamido, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy.

Additional suitable substituents on alkyl, alkenyl, alkynyl, aryl,aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclyl,heterocycloalkyl, and heterocyclyl include, without limitation halogen,CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR¹⁵, NR¹⁵R¹⁶, C₁-C₂ perfluoroalkyl, C₁-C₂perfluoroalkoxy, 1,2-methylenedioxy, (═O), (═S), (═NR¹⁵), C(O)OR¹⁵,C(O)NR¹⁵R¹⁶, OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵, R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, R¹⁷, C(O)H, C(O)R¹⁷, NR¹⁵C(O)R¹⁷,Si(R¹⁵)₃, OSi(R¹⁵)₃, Si(OH)₂R¹⁵, P(O)(OR¹⁵)₂, S(O)R¹⁷, or S(O)₂R¹⁷. EachR¹⁵ is independently hydrogen, C₁-C₆ alkyl optionally substituted withcycloalkyl, aryl, heterocyclyl, aryl, or heteroaryl. Each R¹⁶ isindependently hydrogen, C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl aryl, or heteroaryl. Each R¹⁷ isindependently C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄alkyl or C₁-C₄ alkyl substituted with C₃-C₆ cycloalkyl, aryl,heterocyclyl or heteroaryl. Each C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl and C₁-C₄ alkyl in each R¹⁵, R¹⁶ and R¹⁷ can optionally besubstituted with halogen, CN, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, COOH,C(O)OC₁-C₄ alkyl, NH₂, C₁-C₄ alkylamino, or C₁-C₄ dialkylamino.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed, groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

The compounds disclosed in the present invention are available fromcommercial sources or may be synthesized using reagents and techniquesknown in the art, including those delineated herein. The chemicals usedin the synthetic routes may include, for example, solvents, reagents,catalysts, and protecting group and deprotecting group reagents. Themethods described above may also additionally include steps, eitherbefore or after the steps described specifically herein, to add orremove suitable protecting groups in order to ultimately allow synthesisof the compounds herein. In addition, various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theapplicable compounds are known in the art and include, for example,those described in R. Larock, Comprehensive Organic Transformations, VCHPublishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley and Sons (1999); L. Fieser andM. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, JohnWiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995) and subsequenteditions thereof.

Prodrug Appendage Moiety

In one aspect, a novel design of amine prodrugs is provided in thecurrent invention. In particular, the prodrugs may include a parent drugmolecule having at least one amine group and at least one prodrugappendage moiety attached to an amine of the parent drug molecule.

where R is a prodrug appendage moiety where i may be 1 or 2 and j may be0 or 1. For example, i is 1 and j is 1; or i is 2 and j is 0.

In certain exemplary embodiment, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; R² may be alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; and R² may bealkyl, cycloalkyl, or heteroaryl, or halo alkyl, which may besubstituted or unsubstituted.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; R² may be alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; and R³ may be H, metal, R² or a substituted orunsubstituted primary, secondary or tertiary amine The metal may be Na.K, Li, Ca, Mg, Ag or Zn.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; R² may be alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; and R³ may be H, metal, R² or a substituted orunsubstituted primary, secondary or tertiary amine; and R^(a) or R^(b)may be H, alkyl or aryl, or NR^(a) or NR^(b) may be an amino acid. Themetal may be Na, K, Li, Ca, Mg, Ag or Zn. Aryl, or NR^(a) or NR^(b) maybe an amino acid. The metal may be Na, K, Li, Ca, Mg, Ag or Zn.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; R² may be alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; and X is C or O.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; R² may be alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; and R³ may be H, metal, R² or a substituted orunsubstituted primary, secondary or tertiary amine; and R^(a) or R^(b)may be H, alkyl or aryl, or NR^(a) or NR^(b) may be an amino acid. n maybe 0- b 2.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; and R⁴ may be H,metal, ammonium salt, or alkyl;

In particular, the metal may be Na, K, Li, Ca, Mg, Ag or Zn.

In certain exemplary embodiments, R is,

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; and R⁴ may be H,metal, ammonium salt, or alkyl; k may be 1 or 2, m may be 2-22, or(CH_(k))_(m) may be saturated, unsaturated or conjugated hydrocarbon. Inparticular, the metal may be Na, K, Li, Ca, Mg, Ag or Zn.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl.

In certain exemplary embodiments, R is

In certain exemplary embodiments, R is

In certain exemplary embodiments, R is

In certain exemplary embodiments, R is

where R³ may be H, metal, alkyl, cycloalkyl, aryl, or heteroaryl, orhalo alkyl, which may be substituted or unsubstituted, or a substitutedor unsubstituted primary, secondary or tertiary amine; R^(a) or R^(b)may be H, alkyl or aryl, or NR^(a) or NR^(b) may be an amino acid.

In certain exemplary embodiments, R is

where R¹ may be H, alkyl or particularly C₁-C₈ alkyl; and R⁵ may be asubstituted or unsubstituted natural amino acid;

In certain embodiment, i is 1 and j is 1.

In certain embodiment, i is 2 and j is 0.

In an exemplary embodiment, the amine prodrug may be N-acyloxy carbamateprodrug formed as below.

where R¹ is be H or CH₃; R² is alkyl, cycloalkyl, aryl, or heteroaryl,or alkyl, which may be substituted or unsubstituted.

In certain exemplary embodiments, when the amine of the prodrug is aprimary or secondary amine, the N-acyloxy carbamate prodrug itself mayfurther be converted into an N-acyl compound spontaneously byintramolecular O to N acyl migration. As shown Scheme A, the N-acylcompound may be released as consequence and may substantially provide astable carbamate compound.

In certain exemplary embodiments, the amine prodrugs may have improvedphysiochemical stability, thereby providing advantages in isolation,crystallinity, solid state stability, solubility, formulation and thelike.

In certain exemplary embodiments, the amine prodrugs may have improvedphysiological stability when the prodrugs are taken and ingested by thesubject. For example, the N-acyloxy carbamate drugs may be converted orreleased into the drug form more efficiently in the subject withoutadverse effect.

In certain exemplary embodiments, the amine prodrugs of the inventionmay have specificity to a certain enzymatic reaction. In yet certainembodiments, the prodrugs may be under metabolic pathway to release theactive drug by enzymatic or biochemical reaction.

In certain embodiments, the amine prodrugs of the invention may provideimproved cell permeability to a target cell.

In certain embodiments, the appendage moiety of the amine prodrug mayprovide improved physiochemical stability, improved physiologicalstability, or specificity to particular enzymes.

Riluzole Prodrugs

In one aspect, the current invention provides riluzole prodrugs. Theriluzole prodrug may include a riluzole and at least one or more ofprodrug appendage moieties attached to an amine of the riluzole at itsaromatic amine.

In one embodiment, the riluzole may be coupled to one or more of prodrugappendage moieties (R) to form riluzole prodrugs, in certainembodiments, i is 1 or 2 and j is 0 or 1. For example, i is 1 and j is1; or i is 2 and j is 0.

In certain exemplary embodiment, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted.

In certain exemplary embodiments, R is

where R¹ is H alkyl or particularly C₁-C₈ alkyl; and R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted, and R³ is H, metal, R² or a substituted orunsubstituted primary, secondary or tertiary amine.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; R³ is H, metal, R² or a subsituted or unsubstitutedprimary, secondary or tertiary amine; and R^(a) or R^(b) is H, alkyl oraryl or NR^(a) NR^(b) is an amino acid.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, halo alkyl, which may be substituted orunsubstituted; and X is C or O.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; R³ is H, metal, R² or a substituted or unsubstitutedprimary, secondary or tertiary amine; and R^(a) or R^(b)is H, alkyl oraryl or NR^(a) or NR^(b) is an amino acid.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; and R⁴ is H, metal,ammonium salt, or alkyl. In particular, the metal is Na, K, Li, Ca, Mg,Ag or Zn.

In certain exemplary embodiments, R is,

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R⁴ is H, metal,ammonium salt, or alkyl; k is 1 or 2, m is 2-22 or (CH _(k))_(m) issaturated, unsaturated or conjugated hydrocarbon. In particular, themetal is Na, K, Li, Ca, Mg, Ag or Zn.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl.

In certain exemplary embodiments, R is

In certain exemplary embodiments, R is

In certain exemplary embodiments, R is

In certain exemplary embodiments, R is

where R³ is H, metal, alkyl, cycloalkyl, aryl, or heteroaryl, or haloalkyl, which may be substituted or unsubstituted, or a substituted orunsubstituted primary, secondary or tertiary amine; R^(a) or R^(b) is H,alkyl, aryl or NR^(a) or NR^(b) may be an amino acid.

In certain exemplary embodiments, R is

where R¹ is H, alkyl or particularly C₁-C₈ alkyl R⁵ is a substituted orunsubstituted natural amino acid.

In certain embodiment, i is 1 and j is 1.

In certain embodiment, i is 2 and j is 0.

Exemplary riluzole prodrug may be, but not limited to,

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; R³ is H, metal, R² or a substituted or unsubstitutedprimary, secondary or tertiary amine; R⁴ is H, metal, ammonium salt, oralkyl; R⁶ is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl; k is1 or 2, in is 2-22, or (CH_(k))_(m) is saturated, unsaturated orconjugated hydrocarbon; N′ is a primary, secondary and tertiary aminewhich may be substituted or unsubstituted, or metal salts; and Y isPO₃H, CH₂PO₃H or salt thereof. In particular, the metal is Na, K, Li,Ca, Mg, Ag or Zn.

Synthesis of Riluzole Prodrugs

In one aspect, the riluzole prodrugs may be synthesized via intermediateform.

In one embodiment, the riluzole may be activated to produce anintermediate b reaction with methyl carboxyl group in basic condition.

The intermediate may include a good leaving group, such as halide, andmay be susceptible to a nucleophilic attack from other nucleophiles.Exemplary leaving group may be, but not limited to, Cl, Br, or I.

Exemplary reaction may be described as follows:

In one exemplary embodiment, the riluzole prodrug may be formed byScheme 1. below. In Scheme 1, Compound 1 is reacted with carboxylatemetal to produce Compound 2.

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; and X is Na, K, Li, Ag or Zn. Further, the metal isNa, K, Li, Ca, Mg, Ag or Zn.

In one exemplary embodiment, the riluzole prodrug may be formed byScheme 2 below. In Scheme 2, Compound 1 is reacted with phenylcarboxylate under basic condition to produce Compound 3.

where R¹ is H, alkyl or particularly C₁-C₈ alkyl;Y is PO₃H, CH₂PO₃H orsalts thereof; and Y′ is H, PO₃Bc₂, CH₂PO₂Bc, MPO₃Bc or salt thereof, orN(R_(a))₄ ⁺, where Ra is H or alkyl.

In one exemplary embodiment, the riluzole prodrug may be formed byScheme 3 below. In Scheme 3, Compound 1 is reacted with protectedphosphate and the resulting compound is deprotected to produce Compound3.

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted; R³ is H, metal, R² or a substituted or unsubstitutedprimary, secondary or tertiary amine; and Bc is a protecting group. M isa metal including Na, K, Li, Ca, Mg, Ag or Zn.

In one exemplary embodiment, the riluzole prodrug may be formed byScheme 4 and Scheme 4′ below. In Scheme 4, Compound 1 is reacted withfumarase to produce Compound 5

In Scheme 4′, Compound 1 is reacted with a saturate, unsaturated, orconjugated dicarboxylic acid to produce Compound 5′.

In Schemes 4 and 4′, R¹ is H, alkyl or particularly C₁-C₈ alkyl; R⁴ isH, metal ammonium salt, or alkyl; k is 1 or 2, is 2-22, or (CH_(k))_(m)is saturated, unsaturated or conjugated hydrocarbon; and M is a metalincluding Na, K, Li, Mg, Ca, Ag or Zn.

In one exemplary embodiment, the riluzole prodrug may be formed byScheme 5 below. In Scheme 5, Compound 1 is reacted with protectedaminoacetate and the resulting compound is deprotected to produceCompound 6.

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which may be substitutedor unsubstituted ; and R⁵ is a substituted or unsubstituted naturalamino acid; and M is a metal including Na, K, Li, Mg, Ca, Ag or Zn. Bcis a protecting group.

In one exemplary embodiment, the riluzole prodrug may be formed byScheme 6 below. In Scheme 6, Compound 1 is reacted with aminoacetate toproduce Compound 7.

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; and R⁵ is asubstituted or unsubstituted natural amino acid; and X is Na, K, Li, Agor Zn.

In another embodiment, the riluzole prodrug nay be formed using cesiumcarbonate for carbamination of amine efficiently.

In one exemplary embodiment, the riluzole prodrug may be formed inN-acyloxy carbamate form. In Scheme 7, activated carboxylic acid andcarbon dioxide are condensed with riluzole to form the prodrug (compound8).

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; Lg is a leaving group;R² is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl, which maybe substituted or unsubstituted. In particular, Lg may be a halide, suchas F, Cl, Br and I.

In Scheme 8, riluzole is reacted with 4-methyl 1,3-dioxol-2 one toproduce Compound 9. In an exemplary embodiment, the prodrug may besynthesized as follows.

where R¹ is H, alkyl or particularly C₁-C₈ Lg is a leaving group Lg is aleaving group. Particularly, Lg, may be a halide, such as F, Cl, Br andI.

In Scheme 9, riluzole is reacted with isobenzofurane-1-one to produceCompound 10.

In an exemplary embodiment, the prodrug may be synthesized as follows.

In particular, Lg is a leaving group, Lg may be a halide, such as F, Brand I.

In Scheme 10, riluzole is reacted with ((PhCH₂O)₂PO)₂O and sodiumbis(trimethylsilyl)amide (NaHMDS) and the resulting compound is reactedwith hydrogen gas to produce compound 11.

In an exemplary embodiment, the prodrug may be synthesized as follows:

where R⁶ is alkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl; andN′ is a primary, secondary and tertiary amine which is substituted orunsubstituted, or metal salts.

In one exemplary embodiment, N-acyloxy carbamate prodrug may also besynthesized using

((4-nitrophenoxy)carbonyloxy)methyl formate,where R¹ is H, alkyl or particularly C₁-C₈ alkyl; and R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted orunsubstituted. Exemplary reaction scheme is shown as follows. In Scheme11, riluzole is reacted with ((4-nitrophenoxy)carbonyloxy)methyl formateto produce Compound 12.

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of this invention and are covered by the followingclaims.

We claim:
 1. A prodrug comprising a drug molecule and at least one ormore prodrug appendage moieties, the prodrug is formed as:

wherein the prodrug appendage moiety is coupled to amine of the drugmolecule, and i is 1 or 2 and j is 0 or
 1. 2. The prodrug of claim 1,wherein prodrug appendage moiety is independently selected from thegroup of consisting of:

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted orunsubstituted. R³ is H, metal, R² or a substituted or unsubstitutedprimary, secondary or tertiary amine; R⁴ is H, metal, ammonium salt oralkyl; R⁵ is a substituted or unsubstituted natural amino acid; R^(a) orR^(b) is H, alkyl or aryl; or NR^(a) or NR^(b) is an amino acid; X is Cor O; k is 1 or 2, m is 2-22, or (CH_(k))_(m) is saturated, unsaturatedor conjugated hydrocarbon; n is0-2; the metal is Na, K, Li, Ca, Mg, Agor Zn.
 3. The prodrug of claim 1 wherein i is 1 and j is 1,
 4. Theprodrug of claim 1, wherein i is 2 and j is
 0. 5. The prodrug of claim1, wherein the drug molecule riluzole.
 6. A method of preparing ariluzole prodrug, comprising a step of coupling one or more prodrugappendage moieties to a riluzole molecule

wherein the prodrug appendage moiety is coupled to amine of the riluzolemolecule, and i is 1 or 2 and j is 0 or
 1. 7. The method of claim 6,wherein each prodrug appendage moiety is independently selected from thegroup of consisting of:

where R¹ is H, alkyl or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted orunsubstituted, R³ is H, metal, R² or a substituted or unsubstitutedprimary, secondary or tertiary amine; R⁴ is H, metal, ammonium salt oralkyl; R⁵ is a substituted or unsubstituted natural amino acid; R^(a) orR^(b) is H, alkyl or aryl; or NR^(a) or NR^(b) is an amino acid; X is Cor O; k is 1 or 2, m is 2-22, or (CH_(k))_(m) is saturated, unsaturatedor conjugated hydrocarbon; n is 0-2; is 2-12; and the metal is Na, K,Li, Mg, Ca, Ag or Zn.
 8. The method of claim 6, wherein i is 1 and is 1.9. The method of claim 6, wherein i is 2 and j is
 0. 10. The method ofclaim 6, wherein the riluzole prodrug is selected from the groupconsisting of:

where R₁ is H, alkyl, or particularly C₁-C₈ alkyl; R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted orunsubstituted; R³ is H, metal, R² or a substituted or unsubstitutedprimary, secondary or tertiary amine; R⁴ is H, metal, ammonium salt oralkyl; R⁵ is a substituted or unsubstituted natural amino acid; R⁶ isalkyl, cycloalkyl, aryl, or heteroaryl, or halo alkyl; k is 1 or 2, m is2-22, or (CH_(k))_(m) is saturated, unsaturated or conjugatedhydrocarbon; N′ is a primary, secondary and tertiary amine which issubstituted or unsubstituted, or metal salts; Y is PO₃H, CH₂PO₃H or saltthereof; and the metal is Na, K, Li, Ca, Mg, Ag or Zn.
 11. A method ofsynthesizing a riluzole prodrug, comprising a step of reacting riluzolewith

to produce


12. The method of claim 11, further comprising a step of reacting

with a compound selected from the group consisting of:

wherein R² is H, alkyl or particularly C₁-C₈ alkyl R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted orunsubstituted; R⁴ is H, metal, ammonium salt, or alkyl, k is 1 or 2, mis 2-22, or (CH_(k))_(m) is saturated, unsaturated pr conjugatedhydrocarbon; Bc is a protecting group; Y′ is H, PO₃Bc₂, CH₂PO₂Bc, orsalt thereof, or N(R_(a))₄ ⁺, where Ra is H or alkyl; M is Na, K, Li,Mg, Ca, Ag or Zn; and R′ or R″ are cyclic or acyclic alkyl.
 13. A methodof synthesizing a riluzole prodrug, comprising a step of reacting ariluzole, with CO₂, Cs₂CO₃ and reacting the resulting compound with

wherein Lg is a leaving group.
 14. A method of synthesizing a riluzoleprodrug, comprising a step of reacting a riluzole with

wherein Lg is a leaving group and where R¹ is H, or C₁-C₈ alkyl.
 15. Amethod of synthesizing a riluzole prodrug, comprising a step of reactinga riluzole with

wherein Lg is a leaving group.
 16. A method of synthesizing a riluzoleprodrug, comprising a step of reacting riluzole with

wherein R^(I) is H, alkyl or particularly C₁-C₈ alkyl: and R² is alkyl,cycloalkyl, aryl, or heteroaryl, or halo alkyl, which is substituted orunsubstituted.
 17. A method of synthesizing a riluzole prodrug, colprising a step of reacting riluzole with ((PhCH₂O)₂PO)₂O and sodiumhis(trimethylsily)amide (NaHMDS) and subsequently reacting the resultingcompound with hydrogen:

wherein R⁶ is alkyl, cycloalkyl, aryl,or heteroaryl, or haloalkyl; N′ isa primary, secondary and tertiary amine N, which is substituted orunsubstituted, or metal salts.